Comprehensive microRNA analysis across genome-edited colorectal cancer organoid models reveals miR-24 as a candidate regulator of cell survival

Somatic mutations drive colorectal cancer (CRC) by disrupting gene regulatory mechanisms. Distinct combinations of mutations can result in unique changes to regulatory mechanisms leading to variability in the efficacy of therapeutics. MicroRNAs are important regulators of gene expression, and their...

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Bibliographic Details
Published in:BMC genomics 2022-12, Vol.23 (1), p.1-792, Article 792
Main Authors: Villanueva, Jonathan W, Kwong, Lawrence, Han, Teng, Martinez, Salvador Alonso, Shanahan, Michael T, Kanke, Matt, Dow, Lukas E, Danko, Charles G, Sethupathy, Praveen
Format: Article
Language:English
Subjects:
Animal models
Biological models
Cancer
Cell survival
Cellular control mechanisms
Clinical outcomes
Clinical trials
Colorectal cancer
Colorectal carcinoma
CRISPR/Cas9
Development and progression
Gene expression
Genetic aspects
Genetic modification
Genomes
Genomics
Genotype & phenotype
Genotypes
Health aspects
Heterogeneity
MicroRNA
MicroRNAs
miRNA
Mutation
Oncology, Experimental
Organoid
Organoids
Organs, Culture of
Patients
Precision medicine
Regulatory mechanisms (biology)
Ribonucleic acid
RNA
Survival
Therapeutic targets
Tumor heterogeneity
Tumors
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Summary:Somatic mutations drive colorectal cancer (CRC) by disrupting gene regulatory mechanisms. Distinct combinations of mutations can result in unique changes to regulatory mechanisms leading to variability in the efficacy of therapeutics. MicroRNAs are important regulators of gene expression, and their activity can be altered by oncogenic mutations. However, it is unknown how distinct combinations of CRC-risk mutations differentially affect microRNAs. Here, using genetically-modified mouse intestinal organoid (enteroid) models, we identify 12 different modules of microRNA expression patterns across different combinations of mutations common in CRC. We also show that miR-24-3p is aberrantly upregulated in genetically-modified mouse enteroids irrespective of mutational context. Furthermore, we identify an enrichment of miR-24-3p predicted targets in downregulated gene lists from various mutational contexts compared to WT. In follow-up experiments, we demonstrate that miR-24-3p promotes CRC cell survival in multiple cell contexts. Our novel characterization of genotype-specific patterns of miRNA expression offer insight into the mechanisms that drive inter-tumor heterogeneity and highlight candidate microRNA therapeutic targets for the advancement of precision medicine for CRC.
ISSN:1471-2164
1471-2164
DOI:10.1186/s12864-022-09018-1